Korva is a scroll of the internet’s best ideas.
Naturally low LDL, no heart disease
Too much LDL
The finding built on the opposite condition, familial hypercholesterolemia. These patients typically have total cholesterol around 300 and LDL north of 200, a disease defined by how it looks, since more than 3,000 known mutations produce it. In one form, the protein PCSK9 is hyperactive and constantly destroys the liver's LDL receptors, so LDL runs huge.
Too little LDL
The group Hobbs found was the mirror image, with underactive PCSK9. More of their LDL receptors survived, their LDL stayed at 10 to 20, which corresponds to an ApoB of about 20 milligrams per deciliter, and they never got heart disease, no matter how long they lived.
The drug race
The paper appeared in the New England Journal of Medicine and sent drug companies after a medicine that would mimic it. The antibodies that resulted are wildly effective, the most potent of the cholesterol-lowering drugs.
How did researchers find the PCSK9 variants?
Researchers in Dallas sequenced the PCSK9 gene in participants of the Dallas Heart Study. Jonathan Cohen and colleagues reported in the New England Journal of Medicine in 2006 that Black participants carrying one inactive copy had LDL cholesterol about 28 percent lower than non-carriers. Over 15 years, those carriers also had an 88 percent lower rate of coronary heart disease.
How fast did PCSK9 become a drug target?
In 2003, Marianne Abifadel and colleagues in France reported in Nature Genetics that gain-of-function PCSK9 mutations cause familial hypercholesterolemia. The loss-of-function findings followed in 2005 and 2006. The first PCSK9 antibodies, alirocumab and evolocumab, were approved by the FDA in 2015, about 12 years after the first discovery.
How do PCSK9 antibodies lower LDL?
PCSK9 binds LDL receptors on liver cells and steers them into lysosomes, where they are destroyed instead of returning to the cell surface. The antibodies bind PCSK9 in the blood so it can no longer grab receptors. The receptors keep cycling back to the surface, and each pass pulls more LDL out of circulation.
More from Andrew Huberman
